Osthole ameliorates early diabetic kidney damage by suppressing oxidative stress, inflammation and inhibiting TGF-β1/Smads signaling pathway

• Published in: International immunopharmacology 2024-05, Vol.133, p.112131, Article 112131
• Main Authors: Li, Qiangsheng, Wang, Yifei, Yan, Jia, Yuan, Ruyan, Zhang, Jiamin, Guo, Xinhao, Zhao, Mingming, Li, Fenfen, Li, Xiaotian
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Cell hypertrophy; Cell Line; Coumarins - pharmacology; Coumarins - therapeutic use; Diabetes Mellitus, Experimental - drug therapy; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - pathology; DKD; Fibrosis; Humans; Inflammation - drug therapy; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Osthole; Oxidative stress; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Smad Proteins - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112131

[Display omitted] •Osthole postpones the onset and progression of diabetic kidney disease.•Osthole inhibits oxidative stress and inflammation of diabetic rats.•Osthole alleviates glomerular mesangial cell hypertrophy and apoptosis.•Osthole modulates the TGF-β1/Smads signaling pathway to ameliorate kidney fibrosis brought on by diabetes. Osthole is a natural active ingredient extracted from the traditional Chinese medicine Cnidium monnieri. It has been demonstrated to have anti-inflammatory, anti-fibrotic, and anti-hyperglycemic properties. However, its effect on diabetic kidney disease (DKD) remains uncertain. This study aims to assess the preventive and therapeutic effects of osthole on DKD and investigate its underlying mechanisms. A streptozotocin/high-fat and high-sucrose diet induced Type 2 diabetic rat model was established. Metformin served as the positive drug control. Diabetic rats were treated with metformin or three different doses of osthole for 8 weeks. Throughout the treatment period, the progression of DKD was assessed by monitoring increases in urinary protein, serum creatinine, urea nitrogen, and uric acid, along with scrutinizing kidney pathology. Enzyme-linked immunosorbent assay (ELISA) was employed to detect inflammatory factors and oxidative stress levels. At the same time, immunohistochemical staining was utilized to evaluate changes in alpha-smooth muscle actin, fibronectin, E-cadherin, and apoptosis. The alterations in TGF-β1/Smads signaling pathway were ascertained through western blot and immunofluorescence. Furthermore, we constructed a high glucose-stimulated HBZY-1 cells model to uncover its molecular protective mechanism. Osthole significantly reduced fasting blood glucose, insulin resistance, serum creatinine, uric acid, blood urea nitrogen, urinary protein excretion, and glomerular mesangial matrix deposition in diabetic rats. Additionally, significant improvements were observed in inflammation, oxidative stress, apoptosis, and fibrosis levels. The increase of ROS, apoptosis and hypertrophy in HBZY-1 cells induced by high glucose was reduced by osthole. Immunofluorescence and western blot results demonstrated that osthole down-regulated the TGF-β1/Smads signaling pathway and related protein expression. Our findings indicate that osthole exhibits potential preventive and therapeutic effects on DKD. It deserves further investigation as a promising drug for preventing and treating DKD.